Project summary Human immunodeficiency virus (HIV) infection, the virus causing acquired immune deficiency syndrome, is one of the most important pathogens affecting mankind. Predominantly a disease of poverty, HIV affects young adults in their most productive years and hence also carries a large economic burden. Numbers published by the World Health Organization are bleak: in 2015, approximately 2.1 million new cases of HIV were reported and over 1.1 million people died from the disease. HIV is prevalent in the developing world but it is also resurfacing in wealthy countries, with some 44,073 cases reported in the US in 2014. And yet, there is reason for cautious optimism as the number of new HIV diagnoses has fallen 19% from 2005-2014. HIV can be managed, albeit with a cocktail of 3-4 antiretroviral drugs that need to be taken regularly. Side effects are a concern for these drugs that need to be taken for decades. A large number of patients develop HIV associated neurological disorders (HAND) which results in minor problems with memory to severe dementia-like symptoms. New anti-HIV compounds, selected specifically for their ability to overcome the growing list of HIV strains that are resistant to established drugs, are beginning to populate a small pipeline of potential future drugs but there is certainly a need for more due to the potential to fail in the clinic or earlier. These challenges are best met by combining expertise from the academic and pharmaceutical sectors, which will allow the development of new treatments based on a detailed knowledge of the biology of the virus and best practices in medicinal and computer-aided drug design. The proposed academic-industrial collaboration between the Research Center of Biotechnology RAS, University of Maryland School of Medicine, and Collaborations Pharmaceuticals, Inc. aims to identify new non-nucleoside reverse transcriptase anti-HIV compounds. We have already amassed a considerable body of preliminary data. From a screening library of several thousand compounds, we found 80 hits that display relatively potent anti-HIV activity. Combining traditional genetic and cutting-edge analytical tools, we have already identified the virus targets for some of these hits. The promising novel derivatives will therefore be the initial focus of our effort to turn these into leads (compounds with drug-like properties) using in vitro and computational structure-based approaches, evaluate them for activity in CD4+ T cells (cell lines and primary cells), and in cells that are relevant to neuro-AIDS: primary monocyte-derived macrophages, astrocytes and neurons. We will test the potency of the new NNRTI?s against K103N and other mutants. We will then determine the suitability of the compounds for treating patients with HIV associated neurological disorders using in vitro methods for blood-brain-barrier (BBB) penetration prediction as well as other ADME properties. The resulting compounds will then be further assessed using NIH resources for in vivo testing outside of this proposal.